Biomarker-based asthma phenotypes of corticosteroid response.

BACKGROUND: Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable. OBJECTIVE: We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level) might predict steroid responsiveness. METHODS: The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which Feno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1, a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5'-monophosphate causing a 20% decrease in FEV1 (PC20AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients. RESULTS: Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy. CONCLUSION: A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.

Asthma phenotypes: consistency of classification using induced sputum.

BACKGROUND AND OBJECTIVE: Asthma can be classified as eosinophilic or non-eosinophilic based on the cell profile of induced sputum. This classification can help determine whether corticosteroid treatment is indicated. We assessed the stability of these phenotypes over time and with different treatment regimens. METHODS: Clinically stable, non-smoking, asthmatic adults were enrolled in one of two studies. In study one, induced sputum cell counts from 28 subjects were analysed after 4 weeks without corticosteroid treatment and after 6 week treatments with placebo, regular inhaled beta-agonist, inhaled corticosteroid, and combined beta-agonist and corticosteroid. In study two, sputum from 26 subjects with non-eosinophilic asthma was analysed after 12 weeks of placebo and after four 2-week corticosteroid washouts. Sputum with <2% eosinophils was classified as non-eosinophilic. RESULTS: Sputum classification changed frequently in both studies. In study one, only one of eight participants with non-eosinophilic sputum after placebo treatment remained non-eosinophilic throughout. In study two, all of participants had at least one eosinophilic sputum sample, despite the fact that all had been non-eosinophilic at recruitment. Neutrophilic asthma was uncommon in both studies and was also inconsistent. CONCLUSIONS: The phenotypic classification of asthma changes frequently. A diagnosis of non-eosinophilic asthma should not be based on a single sputum sample.

Simvastatin in the treatment of asthma: lack of steroid-sparing effect.

BACKGROUND: Statins have anti-inflammatory actions which in theory are potentially beneficial in asthma. Small trials have failed to show a significant benefit, but a systematic study to evaluate the steroid-sparing effect of statin treatment has not been carried out. METHODS: A randomised, placebo-controlled, crossover trial was conducted of simvastatin 40 mg at night with simultaneous stepwise reduction of fluticasone propionate dose until loss of control occurred, followed by an increase until regain of control ('minimum' dose required) in 51 patients with asthma and sputum eosinophils (steroid-free) ≥ 2%. RESULTS: 43 patients completed the study. There was no significant difference in 'minimum' inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 µg daily (0-250) vs 100 µg daily (0-250), p=0.931). 'Minimum' dose distribution was similar (p=0.269). The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo (p=0.404). In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 µg daily (0-100) for both, p=0.620). In those patients who reached 0 µg/day (n=18), Astma Control Questionnaire (ACQ) was lower (p=0.037), forced expiratory volume in 1 s (FEV(1)) higher (p<0.01) and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%, p=0.033). CONCLUSIONS: Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils. Clinical trial number ACTRN12606000531516.

Exercise-induced wheeze: Fraction of exhaled nitric oxide-directed management.

BACKGROUND AND OBJECTIVE: Exercise-induced wheeze (EIW) is common. Several treatment options exist. Patients with low fraction of exhaled nitric oxide (F(E)NO) are unlikely to be steroid-responsive and might benefit from non-steroidal therapies. We assessed: the efficacy of cromoglycate, formoterol and montelukast in patients with EIW and low F(E)NO (<35 ppb) in a randomized cross-over trial, and the efficacy of inhaled corticosteroid in a high F(E)NO (>35 ppb) group. METHODS: Patients had EIW and airway hyperresponsiveness (AHR) to mannitol and/or exercise. Those with low F(E)NO (n = 19) received cromoglycate (20 mg inh. bd + before challenge tests), formoterol (12 microg inh. bd + before challenge tests) and montelukast (10 mg p.o. od), each for 2 weeks. Those with high F(E)NO (n = 20) took inhaled fluticasone (500 microg) daily for 4 weeks. Primary end-points were: 50% reduction in maximum FEV(1) %fall (clinical protection) and decrease in AHR to mannitol. RESULTS: In patients with low F(E)NO, cromoglycate, formoterol and montelukast significantly decreased AHR to mannitol in 63%, 61% and 47% of patients, respectively. In this group, the magnitude of exercise-induced bronchoconstriction (EIB) was significantly reduced with montelukast and formoterol; between-treatment differences were not significant. Of 6/19 with low F(E)NO and EIB, protection occurred in 67% (cromoglycate), 83% (formoterol) and 50% (montelukast), respectively. In the high F(E)NO group, AHR to mannitol and EIB decreased significantly with fluticasone (P < 0.001, P = 0.005, respectively), and protection occurred in 7/8 (88%) with EIB. CONCLUSIONS: In patients with EIW and low F(E)NO, the number of 'responders' to cromoglycate, formoterol and montelukast was similar. In a high F(E)NO population the response to inhaled corticosteroid was highly significant and comparable to previous studies.

Effects of steroid therapy on inflammatory cell subtypes in asthma.

RATIONALE Airway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA). OBJECTIVES To assess the inflammatory cell phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; and to investigate changes in sputum cells with inhaled corticosteroid (ICS). METHODS Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000 microg daily for 28+ days. Cut-off points were > or = or <2% for sputum eosinophils and > or = or <61% for neutrophils. RESULTS After steroid withdrawal (n=94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p=0.024). The treatment response was greater in EA for symptoms (p<0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (p=0.007). Lesser but significant changes occurred in NEA (ie, paucigranulocytic asthma). Exhaled nitric oxide was the best predictor of steroid response in NEA for AHR (area under the curve 0.810), with an optimum cut-off point of 33 ppb. CONCLUSIONS After eliminating the effects of ICS and smoking, a neutrophilic phenotype could be identified in patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate the absence of a steroid response. In NEA this was best predicted by baseline exhaled nitric oxide.

The association between obesity and asthma: interactions between systemic and airway inflammation.

RATIONALE: Both obesity and asthma are common conditions, and both are characterized by the presence of inflammation. Animal studies suggest that the development of airway hyperresponsiveness with antigen challenge is exaggerated with obesity. However, clear evidence for either an additive or a synergistic pathologic interaction between obesity and asthma is lacking in humans. OBJECTIVES: To identify whether an interaction between systemic and local inflammation occurs in obese subjects with asthma in a controlled observational study. METHODS: We studied 79 women: obese patients with asthma (n = 20), normal-weight patients with asthma (n = 19), obese patients without asthma (n = 20), and normal-weight patients without asthma (n = 20). After corticosteroid withdrawal, between-group differences in spirometric values, lung volumes, exhaled nitric oxide, induced sputum cell counts, and biomarkers of inflammation in sputum supernatant and blood were measured, and interactions explored. MEASUREMENTS AND MAIN RESULTS: Markers of systemic inflammation were increased with obesity, and Th2 cytokines were increased with asthma, but no important interactions were identified. Obesity adversely affected lung function with increases in functional residual capacity and residual volume in obese but not normal-weight patients with asthma, with a significant obesity by asthma interaction. CONCLUSIONS: The link between obesity and asthma is unlikely to be explained by enhancement of the "classical" forms of airway inflammation resulting from the systemic inflammatory effects of obesity itself. Other mechanisms, possibly related to innate immunity, may explain the relationship between obesity and asthma.

Factors affecting exhaled nitric oxide measurements: the effect of sex.

BACKGROUND: Exhaled nitric oxide (F(E)NO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect F(E)NO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting F(E)NO in a well characterised adult population. METHODS: Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on F(E)NO were explored by unadjusted and adjusted linear regression analyses. RESULTS: The effect of sex on F(E)NO was both statistically and clinically significant, with F(E)NO levels approximately 25% less in females. Overall, current smoking reduced F(E)NO up to 50%, but this effect occurred predominantly in those who smoked on the day of the F(E)NO measurement. Atopy increased F(E)NO by 60%. The sex-related differences in F(E)NO remained significant (p < 0.001) after controlling for all other significant factors affecting F(E)NO. CONCLUSION: Even after adjustment, F(E)NO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.

Association between exhaled nitric oxide and systemic inflammatory markers.

BACKGROUND: Asthma is an inflammatory condition of the airways, and there is some evidence to suggest that it is associated with a systemic inflammatory response, as measured by C-reactive protein (CRP) and fibrinogen. Exhaled nitric oxide is a noninvasive measure of asthmatic airway inflammation. OBJECTIVE: To determine if there is an association between exhaled nitric oxide and these systemic inflammatory markers. METHODS: The Dunedin Multidisciplinary Health and Development Study is a birth cohort of approximately 1,000 individuals born between April 1, 1972, and March 31, 1973. At the age of 32 years, study members were assessed for diagnosis of asthma, atopy by skin prick testing, smoking, body mass index, exhaled nitric oxide, high-sensitivity serum CRP, and plasma fibrinogen level. RESULTS: There was no significant association between exhaled nitric oxide and CRP (P = .99). There was a trend to an inverse association between exhaled nitric oxide and fibrinogen (P = .049), but this was not significant after adjusting for smoking and use of corticosteroids or after further adjustment for body mass index and atopy (P = .71). CONCLUSION: In this population-based sample of young adults, there was no association between airway inflammation, as measured by exhaled nitric oxide, and systemic inflammation, as measured by either CRP or fibrinogen.

Systemic inflammation and lung function in young adults.

BACKGROUND: Impaired lung function is associated with systemic inflammation and is a risk factor for cardiovascular disease in older adults. It is unknown when these associations emerge and to what extent they are mediated by smoking, chronic airways disease, and/or established atherosclerosis. We explored the association between the forced expiratory volume in one second (FEV(1)) and the systemic inflammatory marker C-reactive protein (CRP) in young adults. METHODS: Associations between spirometric lung function and blood CRP were assessed in a population based birth cohort of approximately 1000 New Zealanders at ages 26 and 32 years. Analyses adjusted for height and sex to account for differences in predicted lung function and excluded pregnant women. RESULTS: There were significant inverse associations between FEV(1) and CRP at both ages. Similar results were found for the forced vital capacity. These associations were similar in men and women and were independent of smoking, asthma, and body mass index. CONCLUSIONS: Reduced lung function is associated with systemic inflammation in young adults. This association is not related to smoking, asthma, or obesity. The reasons for the association are unexplained, but the findings indicate that the association between lower lung function and increased inflammation predates the development of either chronic lung disease or clinically significant atherosclerosis. The association between poor lung function and cardiovascular disease may be mediated by an inflammatory mechanism.

Adiposity, asthma, and airway inflammation.

BACKGROUND: Several studies have found obesity to be associated with an increased prevalence of asthma. For reasons that remain unclear, this association has often been reported to be stronger in women than in men. One possible explanation might be that these studies have used body mass index to identify adiposity, which might be a less reliable measure of body fat in men than in women. OBJECTIVE: We sought to explore the association between body fat percentage measured by means of bioelectrical impedance analysis and asthma, airflow obstruction, and airway inflammation in men and women. METHODS: Respiratory questionnaires, spirometry, bronchodilator response, exhaled nitric oxide level, and percentage of body fat were measured in a population-based cohort of approximately 1000 individuals at age 32 years. RESULTS: There was a significant association between the percentage of body fat and asthma in women (P = .043) but not in men (P = .75). Airflow obstruction was associated with percentage of body fat in women (P = .046), but there was an inverse association in men (P = .010). Bronchodilator responsiveness was also associated with lower body fat in men (P = .004). Airway inflammation, measured by means of exhaled nitric oxide, was not associated with body fat in either women (P = .17) or men (P = .25). CONCLUSION: Adiposity is associated with asthma and airflow obstruction in women. This does not appear to be mediated by airway inflammation. In men airflow obstruction and bronchodilator responsiveness are associated with a lower percentage of body fat. CLINICAL IMPLICATIONS: In women, but not in men, obesity is associated with asthma and airflow obstruction, but there was no association with airway inflammation.

Association between exhaled nitric oxide and systemic inflammatory markers.

BACKGROUND: Asthma is an inflammatory condition of the airways, and there is some evidence to suggest that it is associated with a systemic inflammatory response, as measured by C-reactive protein (CRP) and fibrinogen. Exhaled nitric oxide is a noninvasive measure of asthmatic airway inflammation. OBJECTIVE: To determine if there is an association between exhaled nitric oxide and these systemic inflammatory markers. METHODS: The Dunedin Multidisciplinary Health and Development Study is a birth cohort of approximately 1,000 individuals born between April 1, 1972, and March 31, 1973. At the age of 32 years, study members were assessed for diagnosis of asthma, atopy by skin prick testing, smoking, body mass index, exhaled nitric oxide, high-sensitivity serum CRP, and plasma fibrinogen level. RESULTS: There was no significant association between exhaled nitric oxide and CRP (P = .99). There was a trend to an inverse association between exhaled nitric oxide and fibrinogen (P = .049), but this was not significant after adjusting for smoking and use of corticosteroids or after further adjustment for body mass index and atopy (P = .71). CONCLUSION: In this population-based sample of young adults, there was no association between airway inflammation, as measured by exhaled nitric oxide, and systemic inflammation, as measured by either CRP or fibrinogen.